TITLE: EXPLORING EPIGENETIC REGULATION OF MEMORY EXTINCTION PROJECT SUMMARY The broad goal of this proposal is to understand how fear memories are extinguished in the brain. Extinction learning, in which continued exposure to cues associated with an aversive event result in reduced responding to these cues, has been proposed as a way to modify or erase fear memories. However, the molecular mechanisms that control the extinction process remain poorly defined, limiting the therapeutic potential of this behavioral process. Recent evidence suggests that extinction learning requires the functions of neuronal activity induced transcription factors including EGR1 and DNA demethylation enzyme TET1 in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DHPC), though it is unknown how these two mechanisms regulate the extinction process. Our recent study indicated that EGR1 recruits TET1 to remove methylation marks on brain DNA during early postnatal development, though whether such a relationship exists during learning-dependent synaptic plasticity in the adult brain remains equivocal. The purpose of this grant is to explore how these two proteins interact to control memory extinction processes with two specific aims. In Aim 1, the investigators will determine the epigenetic roles of EGR1 and TET1 in the mPFC and DHPC during the extinction of fear memory using a combination of behavioral paradigms in genetic knockout mouse models with whole-genome next generation sequencing approaches. In Aim 2, using targeted CRISPR-dCas9 manipulations in the mPFC and DHPC, the investigators will determine the epigenetic role of EGR1-dependent recruitment of TET1 to the memory permissive gene Npas4 during memory extinction. Collectively, the success of this project will provide novel insights into our understanding of the epigenetic role of Egr1/Tet1 and Npas4 genes during extinction consolidation and significantly broaden our understanding of the mechanisms underlying memory extinction, which could potentially lead to new treatment therapeutic strategies for the treatment fear memories associated with a variety of psychiatric disorders.